Rifaximin (1) {(2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-α]-benzimidazole-1,15(2H)-dione,25-acetate} is a semisynthetic rifamycin-based non-systemic antibiotic marketed in the US as Xifaxan® by Salix Pharmaceuticals.

It is useful for the treatment of travelers diarrhea in adults and in children 12-years of age and older caused by E. coli bacteria. Rifaximin has also been evaluated for the treatment of irritable bowel syndrome, diverticular disease, hepatic encephalopathy, pyogenic skin infections, and as an antibacterial prophylactic prior to colon surgery. Medical News Today has recently published an article detailing a study conducted by physicians at New York-Presbyterian Hospital/Weill Cornell Medical Center using rifaximin for the treatment of patients who suffer from severe Crohn's disease and who have not responded to all other available medications.
Structurally rifaximin is a pyrido-imidazo derivative of rifamycin SV (4-deoxy-4′-methylpyrido[1′,2′:1,2]imidazo[5,4-c]rifamycin SV). Unlike other rifamycin SV derivatives, rifaximin exerts broad spectrum activity and has a specific mode of action which results in low gastrointestinal absorption.
GB 2,079,270 disclose imidazo-rifamycin derivatives having antibacterial activity, prepared from 3-halorifamycin S. U.S. Pat. No. 4,341,785 and EP 0,161,534 (Alpha Farmaceutici SpA) describe the processes for preparing pyrido-imidazo rifamycin starting from rifamycin O. The above patents detail a generic method for the purification of rifaximin in suitable solvent systems such as methylene chloride, chloroform, methanol, ethanol, isopropanol. Water is generally used as an anti-solvent. The polymorphic form of the rifaximin obtained by these methods was not disclosed.
Recently, three polymorphic forms of rifaximin were described in U.S. Pat. No. 7,045,620 (Alfa Wassermann SpA) and designated as α, β, γ. The point of differentiation between these forms is their respective water contents and powder X-ray diffraction (PXRD) diffractogram. These forms are inter-convertible and, therefore, obtaining a specific polymorphic form is dependent on the drying conditions. The γ-form of U.S. Pat. No. 7,045,620 is described as being poorly crystalline with a high content of amorphous component. It is characterized as having a water content between 1.0% and 2.0% and having a PXRD diffractogram containing a few significant peaks at 5.0, 7.1 and 8.4 (two-theta). In particular, this form is prepared by dissolution of in ethanol followed by the addition of water. Also noteworthy is that this form is prone to conversion to other polymorphic forms on exposure to, for instance, due to the change in its water content level. This is a disadvantage since it is highly desirable to have an active pharmaceutical ingredient which is polymorphically stable and suitable for pharmaceutical applications (see Konne, T., Chem. Pharma. Bull., 38, p. 2003, (1990)).
EP 1,698,630 (Alfa Wassermann SpA) teaches two new polymorphic forms (δ, ε). These forms are also obtained from the same process method described above and their specific crystal structures are again dependent of water content and there is a degree of overlap with the other purported forms.
Therefore, it is an object of the present invention to provide a polymorphically pure and stable form of rifaximin, prepared by utilizing industrially acceptable procedures, which overcomes the deficiencies of the prior art.
Further and other objects of the invention will become apparent to those skilled in the art when considering the following summary of the invention and the more detailed description of the embodiments of the invention described herein.